Abstract
Chemotherapy is a mainstay of treatment for solid tumors. However, little is known about how therapy-induced immune cell infiltration may affect therapy response. We found substantial CD45+ immune cell density adjacent to E-selectin expressing inflamed vessels in doxorubicin (DOX)-treated residual human breast tumors. While CD45 level was significantly elevated in DOX-treated wildtype mice, it remained unchanged in DOX-treated tumors from E-selectin null mice. Similarly, intravenous administration of anti-E-selectin aptamer (ESTA) resulted in a significant reduction in CD45+ immune cell density in DOX-treated residual tumors, which coincided with a delay in tumor growth and lung metastasis in MMTV-pyMT mice. Additionally, both tumor infiltrating T-lymphocytes and tumor associated-macrophages were skewed towards TH2 in DOX-treated residual breast tumors; however, ESTA suppressed these changes. This study suggests that DOX treatment instigates de novo intratumoral infiltration of immune cells through E-selectin, and functional blockade of E-selectin may reduce residual tumor burden as well as metastasis through suppression of TH2 shift.
Highlights
Neoadjuvant chemotherapy is indicated for invasive breast cancer treatment as a strategy to improve local control by reducing large, inoperable tumors to a size amenable to surgical resection [1]and to gain systemic control over micrometastases [2,3]
Vessels adjacent to the residual tumor were inflamed as characterized by elevated expression of E-selectin (Figure 1a)
A recent studybreast tumors are associated with shorter disease-free progression time [8], suggesting a possible inverse showed that abundant TILs and tumor associated macrophages (TAMs) in post-chemotherapy residual breast tumors are association between therapy-induced immune cell infiltration and therapeutic response
Summary
Neoadjuvant chemotherapy is indicated for invasive breast cancer treatment as a strategy to improve local control by reducing large, inoperable tumors to a size amenable to surgical resection [1]and to gain systemic control over micrometastases [2,3]. Studies suggest a possible predictive role of pre-treated tumor stroma composition in response to neoadjuvant chemotherapy. Preclinical studies indicated an increase in immune cell density in chemotherapy-treated residual breast tumors, and pharmacologic inhibition of immune cell infiltration improved therapeutic efficacy [6,7,8,9,10,11]. These studies suggest possible negative impacts of therapy-related de novo immune cell infiltration on therapeutic efficacy
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